Oncology Flashcards
Child growing up in Africa presenting with unilateral jaw swelling- what is the likely diagnosis?
Burkitt’s lymphoma (endemic type)
Types of Burkitt’s lymphoma
Endemic (african): jawline/head/neck, 95% chance of EBV
Sporadic: abdomen, 10-15% chance of EBV
Specific Mutation commonly seen in childhood lymphoma
Burkitt’s lymphoma- t(8;14) (q24;q32) reciprocal translation -> C-MYC (Chr8) to Ig heavy chain locus (Chr14). Seen in 80% of Burkitt’s lymphoma
What is the philadelphia chromosome? What is it associated with?
Philadelphia chromosome = t(9;22)
translocation creating BCR-ABL1 causing constitutive activation of Tyrosine kinase to allow unregulated cell division.
Associated with Chronic Myeloid Leukaemia (95% of people with CML have BCR-ABL1) but also seen in Acute Lymphocytic Leukaemia (rarely in AML)
Oncogene examples
RAS, WNT, MYC, ERK, TRK, RET, c-SIS, Raf-kinase, CDKs,
Rtks: EGFR/HER-1, PDGFR, VEGFR, HER2/neu
PI3KCA
Akt1
Tumour suppressor gene examples
Rb, p53, INK4/PTEN, APC, CD95, pVHL
Drugs targeting hallmarks of cancer?
PARP inhibitors: olaparib (for genome instability/mutation)
EGFR inhibitors: cetuximab, gefetinib for sustained proliferative signalling)
VEGF signal inhibitors: bevacizumab (anti-angiogenesis)
Anti-CTLA4 mAb: ipilimumab (immune activating)
What is herceptin?
Trastuzumab = anti HER2 humanised mouse monoclonal antibody
New drug target in melanoma?
B-RAF kinase inhibitors: sorafenib and veramurafenib
B-RAF = Proto-oncogene in MAPK pathway (mutated in 50-60% of melanomas)
Example of targeted cancer immunotherapy?
Programmed cell death receptor (PD-1) and PD-L1 (ligand) overexpressed in many tumours -> decreased cytokine production.
Pembrolizumab and Nivolumab inhibit PD-1 receptor (but severe toxicity)
Ipilimumab anti- CLTA4 antibody. Turns off inhibition of CTLs.
What is taxol?
Inhibitor of mitotic spindle activity, target Tubulin.
Uses: solid cancers (ovary, breast, lung, bladder, prostate, melanoma, oesophageal) + Kaposi’s Sarcoma.
Common mutation seen in melanoma?
B-raf constitutively active in 40-60%
New drug for melanoma?
Vemurafenib. B-RAF enzyme inhibitor (B-RAF-MEK step)
Nivolumab- how does it work? Uses?
Monoclonal antibody inhibiting PD-1 receptor (programmed cell death). Metastatic melanoma, squamous cell lung cancer, renal cell carcinoma.
What does ipilimumab do?
Monoclonal antibody to CTLA4 receptor (normally inhibits cytotoxic T cells)
What is pembrolizumab?
Humanised mouse monoclonal antibody to inhibit PD-1 receptor (programmed cell death) inducing T cell attack.
Common mutation in NSCLC?
Activating EGFR mutation 10-30% (high in non-smokers, adenocarcinoma histology, higher in Japan)
ALK fusion oncogene. (Receptor tyrosine kinase)
What is erlotinib?
Oral EGFR tyrosine kinase inhibitors. Used for specific NSCLCs.
What is gefitinib?
Oral EGFR tyrosine kinase inhibitor used for certain types of NSCLC.
Pathways activated by EGFR?
PI3K -> AKT -> mTOR -> survival
JAK -> STAT ->survival
RAS -> RAF -> MEK -> ERK -> Proliferation
What is glivec?
Imatinib: small molecular inhibitor of BCR-ABL (constitutively active tyrosine kinase) in CML and c-KIT in GISTs.
What is a complete response to treatment?
RECIST for solid tumours
Disappearance of all target lesions.
What is a partial response to treatment?
30% decrease in sum of the longest diameter of target lesions
What is stable disease v progressive disease in solid tumours?
Progressive disease: 20% increase in sum of the longest diameter of target lesions
Stable disease: small changes that do not meet partial response (30% decrease) or progressive disease criteria.
When do we expect Resistance to therapy?
After 10-12months of response to targeted therapy. (Mostly due to ‘steric hindrance’)
How does radiotherapy work?
High energy X-rays interact and produce high energy electrons -> damage DNA directly (ss/ds breaks) and indirectly (cause water -> H. OH. Radicals -> ss/ds breaks)
Side effects fo radiotherapy?
Acute toxicity: after 2w, dermatitis, stomatitis and enteritis. Nausea and fatigue, hair loss (2-3w).
Late toxicity: vascular injury to normal tissues, small vessel obliterative endarteritis and fibrosis.
Growth: premature fusion and loss of stature in children.
Risk of second malignancy: 3% per decade for kids, 1% per decade for adults
How to get maximum radiotherapy dose to tumour?
Conformal: shape the dose
Fractionation of therapy: daily treatments
Enhance by using chemo therapy (chemo-radiotherapy) radiosensitiser.
Example of nitrogen mustard? MOA?
Cyclophosphamide, melphalan, chlorambucil, bendamustine
MOA: DNA alkylators
Alkylating agents for chemotherapy?
Nitrosoureas: nimustine, carmustine, lomustine
Triazene: dacarbazine, procarbazine, streptozotocin - alter bases
Nitrogen mustards: chlorambucil, cyclophosphamide, melphalan, bendamustine
Aziridines: Mitomycin C, thiotepa
Modify purines, guanine/adenine alkylation and chemical crosslinking.
Antifolate and purine analogues for cancer therapy?
Antifolates: methotrexate (DHFR)
Purine analogues: 5-fluoro-uracil.
PrPP/GARFT pathway: 6-mercaptopurine
Platinum agents in cancer therapy? Which? MOA?
Cisplatin, carboplatin
MOA: intrastrand DNA cross-link, interstrand DNA cross-link, DNA histone crosslinks, induction of apoptosis.
Anthracyclines in cancer therapy?
Doxorubicin, (red fungus from adriatic)
Intercalates into DNA and inhibits Topoisomerase I and induces free radicals. Cardiotoxic
What are taxanes?
Taxol/paclitaxol. Microtubule formation inhibitor = mitotic arrest.
Not water soluble. (Frequent systemic allergic response)
Used for solid tumours
What are Camptothecins?
Topoisomerase I inhibitors. (Prevents DNA uncoiling before replication). Irinotecan/topotecan.
What is gemcitebine?
Synthetic nucleoside analogue (instead of C- blocks DNA synthesis)
Uses: bladder/urothelial. Pancreatic cancer.
Causes early neutropaenia
What is the difference between cytocidal and cytostatic agents?
Cytocidal: direct reduction in number of clonogens, kills cells. Mainly during replication
Cytostatic: prevents tumour growth, inhibiting growth signal or disrupt blood supply. Cell kill secondary.
What type of agents are cytocidal, cytostatic?
Cytocidal: most chemotherapy
Cytostatic: many biological therapies
What affects sensitivity of tumours to cytotoxic agents? Which tumours?
Rate of cell division.
High: lymphoma, leukaemia, SCLC, testis
Mid: Breast, colorectal, NSCLC
Low: HNSCC, prostate, stomach, pancreas, glioma
What is an important consideration when treating Burkitt’s lymphoma?
Burkitt’s lymphoma is very sensitive to chemo- beware of tumour lysis syndrome (hyperuricaemia, renal failure)
How does the number of cells killed by cytoxic agents change with doses?
Constant FRACTIONof cells killed by a certain dose of drug. Need repeated doses for tumour control.
Difference in adjuvant v curative primary chemotherapy?
Curative chemo: enough doses to reduce tumour cell number to zero through cumulative cell kill.
Adjuvant: less doses need to bring tumour clonogen number to zero.
How do we generally dose chemotherapy?
Body surface area (decent surrogate for drug clearance)
Biologics may be dosed by body weight.
Carboplatin dosed by GFR
What is MTD? What is LC50?
MTD: maximum tolerated dose (of chemo)
LC50: lethal concentration determined in animal models.
Why 3 weekly cycles of chemo?
3 weeks for bone marrow to recover.
What is dose intensity? Dose density?
Intensity: increasing dose a little
Density: decrease interval between doses.
Complication of procarbazine?
Delayed bone marrow suppression (given 6weekly cycle)
How to ablate bone marrow?
High dose chemo (above MTD) then rescue with stem cell transplant
What is primary restistance to chemotherapy?
No response from the start
What is acquired resistance in chemotherapy? What do you do about it?
Adaption/mutation of tumour clonogens.
Combination chemo/sequenced chemo to overcome resistance.
Mechanisms of acquired tumour resistance?
- enhanced drug efflux (p-glycoproteins transporters)
- Multidrug resistance protein
- Compartmentalisation (reduced uptake of agent to nucleus)
- Upregulate target enzyme/pathway
- rapid repair of DNA lesions
- Abrogation of apoptosis pathway
Mechanism of nausea in chemo?
Area postrema near 4th ventricle. (No tight junctions in vessels: ‘samples’ circulating blood)
Management of nausea/vomiting in chemo?
Ondansetron: 5HT3 antagonists
If needed can use Aprepitant (NK1 receptor antagonist)
Highly emetogenic regimens?
Cisplatin, dacarbazine, streptozocin, ABVD, AC, BEP. = use 5HT3 antagonists
Acute toxic effects of chemo?
Nausea and vomiting
Skin/mucosa: mucositis, alopecia, extravasation
Bone marrow: anaemia, neutropaenia, thrombocytopaenia
GI: Diarrhoea, constipation, typhlitis
Neuro: encephalopathy
Systemic allergic response
Tumour lysis syndrome
What is typhlitis?
Neutropaenic enteritis
Important effect of ifosfamide?
Encephalopathy
Important early effect of taxanes?
Systemic allergic response
Signs of tumour lysis syndrome?
Hyperkalaemia
Hyperuricaemia
Metabolic acidosis
Renal failure
How to avoid tumour lysis syndrome?
Prehydration, give chemo slowly
Urinary alkalinisation (allows increased uric acid secretion)
Allopurinol before chemo (inhibits uric acid production)
Late toxic effects of chemo?
Cardiac, renal, hepatic, lung fibrosis, nerve toxicity and deafness, fertility impairing, carcinogenicity and teratogenicity.
Important late effect of bleomycin?
Lung fibrosis
Chemo agents causing nerve toxicity and deafness?
Vincristine, oxaliplatin, cisplatin
Important late effect of anthracyclines?
LVEF
Important late effect of 5-FU?
Coronary arteries affected
Chemo agents toxic to kidney late?
Cisplatin, carboplatin,
Carmustine
Methotrexate (high dose)
Types of biological therapies?
Monoclonal antibody therapies (-ab)
Small molecular inhibitors of tyrosine kinases (-ib)
Non-specific immune activation (interferon, interleukin)
Specific vaccines
What is a targeted biological therapy?
Targeted to pathway highly upregulated or specific to cancer cells.
Mechanism of monoclonal agents action?
PN humanised monoclonal -> immune activation by CTLA-4 binding and cytotoxic T cell activation.
What is avastin?
Bevacizumab: monoclonal to VEGF-A. Prevents VEGFR-2 binding. Use: colon, lung, breast, kidney, GBM, AMD.
Problem with avastin?
Pseudoresponse: initial dramatic response, not maintained. Initial separation of survival curves lost at 12m.
Other issues: impaired wound healing, HTN, proteinuria, renal injury
What is herceptin?
Trastuzumab: Monoclonal antibody to HER-2/neu receptor (prevents EGF binding)
Use: HER2+ metastatic or high risk breast cancer
Important problem with herceptin?
Rare myocardial toxicity. (Espcially if prior anthracyclines treatment)
What is gefitinib?
Iressa/gefitinib: inhibits Tyrosine kinase of EGFR.
Useful for EGFR + mutation NSCLC
What is Glivec?
Glivec/Imatinib: tyrosine kinase inhibitor for BCR-ABL fusion protein (constitutively active). Philadelphia chromosome + CML.
Also Used for GISTs: targets c-KIT
How to see response to glivec?
PET imaging. Tumours may be same size on CT.
Is resistance a problem in biological therapies?
YES: resistance to Tyrosine Kinase inhibitors after approx 8-12months. (By steric hindrance)
Pt currently being treated for cancer presents to ED: what is the most important question you want to know?
Are they on curative or palliative treatment
Definition of neutropaenic sepsis?
- ANC (absolute neutrophil count) <0.5 (or less than 1.0 and expected to go <0.5) AND
- A: Temp >38C on 2 occasions or >38.5 once OR
- B: Hypotension, desaturation, organ failure
Pt being treated for metastatic colorectal cancer presents to ED feeling rubbish. Day before new cycle of chemo. Differentials?
GI Gram negative neutropaenic sepsis-> tazocin
Urosepsis
Pneumonia
Likely causative organism in pt treated with PICC for cancer? Which antibiotic to use?
Staphylococcal sepsis -> use vancomycin
Organisms seen in haematological cancer treated patient
Fungal infections (including pneumocystis pneumonia)
Cancer pt presenting with appendix like symptoms - differentials?
Perforation
Neutropaenic enteritis
Appendicitis
Management of ?neutropaenic sepsis?
Peripheral and central blood cultures IV antibiotics (piperacillin/tazobactam) \+ gentamycin if hypotensive \+ vancomycin if PICC/portacath 4hrly Obs + MEWS \+ GCSF if pt is shocked Regular review DON'T do a PR = risk of bacteraemia
Signs of malignant hypercalcaemia?
Bones (bone pain, even if no mets), stones (renal stones, hypercalinuria), groans (abdo pain), psych moans (depression), malaise
Best Clinical indication of spinal cord compression?
Short history of radicular (band-like) pain with a sensory level.
Signs/symptoms of spinal cord compression?
Pain +sensory level. Bone tenderness Distal weakness Hyper-reflexia Bladder and bowel disturbance
Management of spinal cord compression?
Analgesia, bed rest
Start dexamethasone to reduce cord inflammation and oedema
Urgent MRI spine with contrast (or CT myelogram if pacemaker)
(Catheter)
Refer to MSCC
Surgery or radiotherapy.
Why choose surgery or radiotherapy in malignant spinal cord compression?
Surgery: best for single level disease (especially if vertebral collapse -> restore vertebral geometry)
Radiotherapy: for extensive multi-level disease, poor performance status/high disease burden or soft tissue masses
Causes of malignant hypercalcaemia?
Diffuse bone disease
Paraneoplastic syndrome from ectopic PTHrP (lung cancer/NET)
Treatment of malignant hypercalcaemia?
Fluid rehydration (4l or more -> pt euvolaemic) Bisphosphonate therapy (inhibits osteoclasts activity) may be also used to prevent hypercalcaemia and fractures Treat tumour (good for refractory hypercalcaemia)
Tumours at risk of tumour lysis syndrome:
Burkitt’s Lymphoma
Germ cell tumours
Treatment of tumour lysis syndrome?
Rasburicase: recombinant uric oxidase (urate -> allantoin =10x more soluble and excretable) BUT expensive
Causes of hyponatraemia in cancer patients?
Corticosteroid induced hyponatraemia (given in advanced disease)
Pt with losses: 3rd space-oedema, D+V
Disease in lung, liver, brain
SIADH from ectopic ADH production
How to differentiate the causes of hyponatraemia in malignancy?
Hypovolaemic hyponatraemia: steroids, D+V, oedema, ext disease.
Euvolaemic hyponatraemia: SIADH
Technically true but difficult to use clinically (e.g. Dehydrated patient, non specific symptoms)
-> PAIRED URINE PLASMA OSMOLALITY
Expected result in SIADH of paired urine and plasma osmolality?
Inappropriately concentrated urine for hyponatraemia
How to manage ?SIADH?
Treat underlying malignancy
Liaise with endocrinology re fluid restriction and democlocycline (tubular poison)
Important neuro sign of hydrocephalus?
False localising CNVI palsy
Signs/symptoms of raised ICP?
Headache (on waking in morning) Nausea Seizures Focal neuro deficit (false localising CNVI palsy) Behavioural change Fluctuating level of consciousness Papilloedema
Radiological signs of acutely raised ICP?
Dilated ventricles, sulci NOT effaced
Periventricular fluid transudation (bright on T2) ‘capping sign’
How to diagnose ?hydrocephalus?
Urgent CT
Management of hydrocephalus?
Ommaya reservoir: fluid drainage at bedside, allows intrathecal chemo
Ventriculo-peritoneal shunt: long term if chronic hydrocephalus. Programmed valve. (No longer ventriculoatrial shunts -sepsis)
Endoscopic third ventriculostomy: for tumour blocking ventricular outflow, CSF to basal cisterns,
Likely cause of SVCO today?
Bulky mediastinal lymph nodes in SCLC. (Previously syphilitic aortitis)
Pt with lung cancer presents with dyspnoea, headache, dizziness. Differentials?
SVCO Progression Hydrocephalus/raised ICP Pneumonia Cardiac disease?
Signs of SVCO?
High venous pressure
Headache and dizziness
Facial swelling and redness
(Dilated veins of chest wall if longer time span)
Management of SVCO?
Sit up
Oxygen (high flow)
High dose steroids
- clinical diagnosis (CXR/CT for confirmation)
Discuss with interventional radiologists ?stent OR start definitive treatment if a mural thrombus.
What circumstances would allow you to not discuss DNACPR?
‘Serious physical or psychological harm’
Cancers that metastasise to bone?
Breast Kidney Thyroid Bronchus Prostate
Cytokeratin markers for breast cancer?
CK7+, Oestrogen-R +, Progesterone-R +
Cytokeratin markers for breast cancer?
CK7+, Oestrogen-R +, Progesterone-R +
